Sterile water for injection (SWFI) is an essential component in reconstituting freeze-dried blood products and in the preparation of “parenteral solutions” (i.e., solutions introduced into the human body such as intravenous fluids). The production of SWFI is a significant problem for medical personnel operating under field conditions such as in combat or during disaster relief operations. The solution of this problem requires a compact, reliable, and automatic system that can continuously produce SWFI from available water sources under field conditions. For example, an efficient and compact fluid processor is essential to meet the field deployment requirements for a system to produce SWFI as set forth in the United States Navy's requirements for a SWFI generator. See, RFP Navy STTR N99-T008. Such a fluid processor should also incorporate a heat sterilization operation as the final processing step as preferred by the United States Food and Drug Administration (“FDA”). See, Inspectors Technical Reference No. 40, FDA (1985). This thermal treatment feature would have a positive impact on obtaining FDA approval of such a device. In addition, such a system must be easy to maintain and operate, and have low energy requirements for operation.
In order to meet regulatory requirements, (see, United States Pharmacopoeia XXIV) SWFI must be sterile (i.e., free of all living micro-organisms) and free of particulate matter, oxidizable substances, dissolved gases, metals and electrolytes. In addition, SWFI must be rendered free of pyrogens (“depyrogenated”). Also known as bacterial endotoxins, pyrogens are metabolic products of living micro-organisms or dead micro-organisms. Chemically, pyrogens are lipopolysaccharides (“LPS”). The term “pyrogen” (i.e., fever-producing agent) is derived from the fact that if a parenteral product containing pyrogens is injected into a patient, a rapid rise in body temperature occurs after a latent period of about one hour, followed by chills, headache, and malaise. Pyrogens lose little of their potency over the years and effective depyrogenation requires high temperatures and long holding times.
Sterilization and depyrogenation of water can be accomplished by physical methods (e.g., heat), chemical agents (e.g., ethylene oxide, formaldehyde, alcohol, and ozone), radiation (e.g., ultraviolet radiation) or mechanical methods (e.g., filtration). Present systems for manufacturing SWFI generally employ distillation or reverse osmosis (“RO”) methods for depyrogenation in combination with additional treatment steps, typically involving active carbon filters, deionizers, and ultrafiltration filters. However, distillation and RO systems only separate pyrogens from water. Pyrogen residues remain in these systems in the form of distillation still residue or reverse osmosis retentate. Thus, these systems must be continually or periodically purged in order to remove these pyrogen residues. This requirement makes these systems unsuitable for use under field conditions. These systems also have other disadvantages that make them unsuitable for use in the field.
Distillation systems are generally highly energy intensive and require a number of system components such as heat exchangers, evaporators, condensers, and vapor compressors. These components are either bulky or difficult to use or maintain in the field. Also, recuperating thermal energy is the most critical factor in a practical distillation system. Consequently, distillation systems generally use vapor compression and plate-and-frame heat exchangers since this combination is effective in improving the thermal efficiency of conventional distillation processes. However, plate-and-frame heat exchangers do not comply with the heat exchanger design guidelines established by the FDA for continuous production of SWFI. See, Inspectors Technical Guide No. 34, FDA (1979). Therefore, the product water produced using heat exchangers other than those recommended by FDA must be collected and batch validated before use. See, Inspectors Technical Guide No. 34, FDA (1979).
As for RO systems, these require periodic changing of the filters in order to remain effective. Moreover, RO filters are not entirely satisfactory. In particular, RO systems lack a final heat sterilization capability that is currently required for approval by the FDA. Generally, RO systems are water for injection (“WFI”) systems that operate at ambient temperatures. Such relatively low temperature systems present a problem because many objectionable micro-organisms that are good sources of endotoxins grow well in cold WFI. See, Inspectors Technical Guide No. 40, FDA (1985). Thus, to prevent microbial growth WFI is usually produced in a continuously circulating system maintained at an elevated temperature that must be at least 80° C. to be considered as acceptable. See, Inspectors Technical Guide No. 46, FDA (1986). Other RO systems require the use of special filters. For example, U.S. Pat. No. 4,810,388 to Trasen and U.S. Pat. No. 5,032,265 to Jha, et al. both disclose depyrogenating water using RO and then passing the water through a sterilizing filter instead of using heat in order to sterilize the water. Current practice in the U.S. to produce SWFI by the RO method requires a two-stage RO separation process (in series) followed by ultra-violet (“UV”) sterilization. The foregoing limitations make RO systems unsuitable for a SWFI production system to be used in the field.
Other depyrogenation methods require adding substances (i.e., “depyrogenating agents”) to water in order to depyrogenate the water. However, these depyrogenating agents have to be removed from the water after completion of the depyrogenation process. This makes this method more complicated and not easy to use in the field. For example, U.S. Pat. No. 4,935,150 to Iida, et al. discloses adding calcium salt to water to remove pyrogens and then later removing the resulting precipitate. U.S. Pat. No. 4,648,978 to Makinen, et al. discloses depyrogenating water by adding an oxidant selected from the group consisting of hydrogen peroxide and ozone and heating the solution. The resulting solution requires further processing to remove the oxidant.
Another method of depyrogenation involves passing water through materials that adsorb pyrogens. See, for example, U.S. Pat. No. 5,498,409 to Hirayama, et al. and U.S. Pat. No. 5,166,123 to Agui, et al. However, this method has the same disadvantage as apparatus that use distillation and RO methods in that the use of adsorbents only separates pyrogens from water. The concentrated pyrogen (hereafter, “isolated pyrogen”) that has adhered to the adsorbents still has to be disposed, purged, or destroyed (i.e., chemically altered or degraded to permanently lose their potency as pyrogens).
Pyrogens in water can also be destroyed by subjecting the water to high temperature under pressure. This method of water treatment is called hydrothermal processing (“HTP”). U.S. Pat. No. 4,070,289 to Akcasu discloses a method of depyrogenation by heating water in a sealed, pressurized container. However, Akcasu does not allow for the continuous production of depyrogenated water. At most, the process disclosed in Akcasu can be operated as a “semi-batch process”. That is, two containers are operated in parallel wherein external cooling water flows between the two containers in series, cooling down the treated water in the first container and subsequently pre-heating the water to be treated in the next container. In addition to being unable to continuously produce depyrogenated water, the foregoing configuration of containers results in a fluid processor that is bulky and not suitable for use in the field. U.S. Pat. No. 6,167,951 to Couch et al. discloses a depyrogenation process involving heating water followed by catalytic wet air oxidation. However, the heating step requires a specially designed heat exchanger rather than a standard heat exchanger. This makes the process more complicated and expensive. Further, the oxidizing step requires exposing the heated water to a wet oxidation catalyst in a reactor with sufficient air or oxygen. However, contacting water with the catalyst could result in the dissolution of certain components of the catalyst into the water being processed, and hence increasing the risk of contaminating the resulting product water. This is of particular concern if the intention is to produce SWFI. Furthermore, the wet air oxidation process requires high-pressure air or oxygen that must be generated by a compressor or other similar source. This would increase the complexity of an SWFI production system to be used in the field.
There are other depyrogenation methods involving high-temperature processing steps. However, these require additional treatment of the heated water in order to remove pyrogens. For instance, U.S. Pat. No. 6,485,649 to Tereva, et al. discloses a process involving sterilization of water by heating water and the passing the heated water through a thermally stable filter to remove pyrogens. Such apparatus are not satisfactory for field use since they require multiple steps to depyrogenate water or require frequent changing of filters to ensure depyrogenation. This makes them more complicated and difficult to maintain in the field.
Apparatus used for producing SWFI must also be sanitized on startup to eliminate any micro-organisms that may have developed in the apparatus during storage. These apparatus must also be properly shut down and sealed after use in order to prevent contamination and the growth of micro-organisms during storage. Steam and dry heat are widely used means of for sterilizing SWFI equipment. Generally, present systems for producing SWFI require disassembly and sanitization of the individual components to ensure proper sanitization. This makes it difficult to use these apparatus under field conditions where proper sanitizing equipment or facilities are not readily available.
The processing of fluids (e.g., depyrogenating water) also requires a process control system. This is because any chemical or physical process, particularly the ones used in the field, is ideally operated in a convergingly stable domain such that minimum operator intervention is required. The stability of a fluid process is commonly characterized by four basic variables: temperature, pressure, flow rate, and level of the fluid being processed. In general, the critical process parameters for a high-pressure fluid processor are pressure, flow rate and temperature.
Current process control systems fall into two categories. In the first category are process control systems such as the system shown in FIG. I which are precise, but which require elaborate and complex sensors 10 and control valves 12, 14. The final control element for flow rate and pressure is generally an automatic control valve 14 having a throttling action operated electrically or pneumatically in response to readings from a sensor 10. Automatic control valves are relatively bulky, complex, and prone to mechanical failure. Thus, a system equipped with automatic control valves is not compact, robust, simple to operate or maintain. In the second category are process control systems that use simple mechanisms but which are not precise or reliable and which require frequent adjustment. For example, FIG. 2 shows a simple pressure-control system that does not have pressure sensor feedback and which uses a pressure-relief valve 16 (typically a spring-loaded type) in place of an automatic control valve. This system often shows pressure fluctuation and/or drifting, and requires frequent adjustment of the pressure relief valve.
In order to overcome the disadvantages of the prior art, it is the principal object of the present invention to provide an apparatus and related method for hydrothermal production of SWFI that is compact, reliable, easy to maintain and operate and which has low energy requirements. In particular, it is a specific object to obtain an SWFI fluid processor having a reliable, simple and compact process control system that is suitable for the continuous depyrogenation and production of SWFI using HTP without producing isolated pyrogen or requiring additional steps for depyrogenation. It is the further object to obtain an SWFI fluid processor that has built-in features and simple procedures for both sanitizing the system during a cold start, and for maintaining system sterility during shutdown, storage, and restart.